Development of autoimmune diseases requires coordinated expression of a myriad of genes. Expression of these genes is regulated by several families of transcription factors, which in combination orchestrate the initiation, progression and remission of the diseases. The long-term goal of our research is to elucidate the mechanisms of transcriptional regulation of autoimmune diseases. This proposal is based on our recent discovery that mice deficient in p53, a pivotal transcriptional regulator of apoptosis and cell proliferation, develop exacerbated autoimmune encephalomyelitis and arthritis and are defective in TH2, but not TH1, responses. The goal of this proposal is to elucidate the mechanisms of p53 action in animal models of multiple sclerosis (MS). A major challenge to study the roles of transcription factors in autoimmune diseases is that they are often expressed by a variety of cell types that perform different functions. In the case of p53, it is expressed not only by cells of the immune system, but also by cells of target organs such as brain and spinal cord. The roles of p53 in different cell types must be established before a comprehensive understanding of p53 action in autoimmunity can be achieved. We hypothesize that p53 expressed by immune cells and neural cells may play different roles in encephalomyelitis: p53 expressed by immune cells inhibits inflammation and prevents neural tissue injury, whereas p53 expressed by neural cells promotes inflammation-induced tissue injury. To test this hypothesis, we will study 1) roles of p53 expressed by the immune system and central nervous system in EAE, 2) roles of p53 in the activation and differentiation T cells, and 3) roles of p53 in the death and survival of T ceils and oligodendrocytes. Information generated from these studies may not only help elucidate the mechanisms of p53 action in EAE but also aid in developing a general strategy to investigate the roles of transcription factors in autoimmune diseases. Novel strategies targeting p53 may then be developed to treat or prevent autoimmune diseases.